Sulfonamidotryptamines



United States Patent U.S. Cl. 260326.12 9 Claims ABSTRACT OF THEDISCLOSURE Tryptamines and N-substituted tryptamines bearing asulfonamide substituent in the 4, 5, 6 or 7 positions of the indole ringhave hypotensive, intestinal relaxant, and central nervous systemdepressant activity.

Tryptamine has been known for many years as a biological productinvolved in the intermediary metabolism of proteins, specifically of theamino acid tryptophan. One of the identified functions of tryptamine isan intermediate in formation by the animal organism of biologicallyactive hydroxylated derivatives such as serotonin. The present inventionprovides a novel group of biologically active compounds havingstructures resembling tryptamine.

The compounds of this invention are represented by Formula I whichappears below. The sulfonamide function illustrated by R SO NR occupieseither the 4-, 5-, 6-, or 7-positions R is hydrogen, benzyl, or loweralkyl having up to 4 carbon atoms R is hydrogen, lower alkyl having upto 4 carbon atoms, or carboxyl.

The symbol refers to an N-substituted heterocyclic group having up to 7carbon atoms, an N-substituted heteropolycyclic group having up to 11carbon atoms, or an amino group in which R and R may be the same ordifferent. Morpholino, pyrrolidino, piperazino, tetrahydroquinolino, andtetrahydroquinazolino are representative of heterocyclic andheteropolycyclic groups. R is hydrogen, benzyl, or lower alkyl, or loweralkenyl of up to 4 carbon atoms. R is hydrogen, alkyl, alkenyl, alkynyl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl,polycycloalkyl, polycycloalkenyl, polycycloalkylalkyl,polycycloalkenylalkyl, aryl, aralkyl, aralkenyl, aryloxyalkyl,heterocyclic, heterocycloalkyl, heteropolycyclic, orheteropolycycloalkyl, each containing up to 12 carbon atoms, and havingup to two substituents selected from hydroxyl, carboxyl, amino, loweralkoxy having up to 4 carbon atoms, lower alkyl having up to 4 carbonatoms, and methylenedioxy.

R is alkyl, alkenyl, cycloalkyl, or cycloalkenyl each having up to 6carbon atoms, phenyl, phenylalkyl, naphthyl, substituted phenyl,substituted phenylalkyl, or substituted naphthyl, wherein saidsubstituent is alkoxy, alkyl, alkenyl, cycloalkyl, or cycloalkenylhaving up to 6 carbon atoms, halogen, or benzyloxy. R is hydrogen orlower alkyl having up to 4 carbon atoms.

Alk is an alkylene group of 2 to 6 carbon atoms with at least 2 carbonatoms separating the indole ring and the aminonitrogen substituent Alkmay be straight or branched.

3,472,870 Patented Oct. 14, 1969 The compounds identified by Formula Ipossess hypotensive, central nervous system depressant, and smoothmuscle depressant properties. They are relatively nontoxic, having acutetoxicities for mice in the range of 250 to more than 2000 mg./kg. by theintraperitoneal and oral routes. Their pharmacologic effects are,however, elicited in doses below the toxic limit. They are preferablyadministered by the parenteral routes, although absorption thereof fromthe alimentary canal following oral or rectal administration ispossible.

The process for the preparation of the compounds of Formula I involvesthe unitary concept of reducing or hydrolyzing a functional side chainin the 3-position of an indole containing a sulfonamido group (R SO N-Rin the 4-, 5-, 6-, or 7-positions. The functional chain in the3-position is so constituted as to provide an aminoalkyl group,

Alk-N of the character shown in Formula I on reduction by chemical orcatalytic means, or hydrolysis. Reducible side chains includecyanoalkyl, nitroalkenyl, oxamyl, and acylalkyl. Carboxamido alkyl sidechains are contemplated for use in the hydrolytic variation. The processconcept is illustrated in the following diagram.

Genealized Reaction Scheme I -alkC)O, and AlkN-COR a a RJSOaN wherein Ris lower alkyl and the other symbols have the meaning already assigned.

In those applications of this process employing the cyanoalkyl,nitroalkenyl, or oxamyl intermediates, chemical or catalytic reductionmethods known for the transformation of nitriles, nitro compounds, andcarboxamides to amines are applicable. Catalytic methods employ eithernoble metal or Raney nickel catalysts. Platinum oxide catalyst is quiteappropriate in low pressure (15-60 p.s.i.) hydrogenations. In the caseof the acylalkyl intermediates, catalytic reduction employing preferablya platinum catalyst is employed and the process is carried out in thepresence of a primary amine under the conditions ordinarily used for thepreparation of secondary amines by reductive alkylation. Chemicalreduction methods use any of a variety of reagents known to the art forthis purpose, but the hydrides such as lithium aluminum hydride anddiborane are the most convenient for small scale Work.

For simplicity of illustration, the description of the synthesis ofspecific compounds of the present invention is subdivided according tothe method used for synthesis of the intermediates of Formula II. Fivegeneral methods 3 4 are employed to prepare the intermediates. These(Reactions 11-15), reductive alkylation (Reactions l6- methods are shownbelow in schematic fashion and illus- 19), and the Fisher indolesynthesis (Reactions 20-25). trated by specific working examples whichfollow. They The first four methods involve reduction variations of theare the gramine synthesis (Reactions 1-6), the Vilsmeier generalizedscheme. The Fischer synthesis employs a aldehyde synthesis (Reactions7-10), the oxamyl method 5 hydrolytic final stage.

GRAMINE SYNTHESIS (Reactions 1-6) (I) ommonm (2) CHzCN (3) CHZCN NO NONO NH N Ra N/ R2 N/ R2 N it (6) OH CH NH (5) 0H20N FORMULAI t- R som IR5SO2N l N/ R2 R2 1 VILSMEIER ALDEHYDE SYNTHESIS (Reactions) (7) CH0 (8)CH=CNO1 (g) crnomvn, msozN R soiN R SOzN R som f f W T R1 R1 1 1 11 lflFORMULA I OXAMYL SYNTHESIS (Reactions 11-15) R4 Rt 000001 GOCON/ COCON/NO No, No, NH

y W R1 R1 R1 iv R1 R FORMULAI (15) cOCON\ R5SO2N REDUCTIVE ALKYLATION(Reactions 16-19) f OH=C-NO (16) 011,00 msoiN i L R soiN J: L

R1 R1 N N I i '0 amine, R4

f omoHnHi (18) orncmmm (19) Iusom J: W R5SON FORMULA! a e 60! N R2ketong, R N R2 FISCHER SYNTHESIS (Reactions -25) (24) R 8 O2N F RMULA IIn the foregoing reaction diagrams, Reactions 5, 9, 15, and 17 arerepresentative of reduction methods conforming to the generalizedreaction scheme illustrating the unitary process concept. Reaction 24 isillustrative of a hydrolytic method. Reactions 6, 10, 18, 19, and 25 arealternative supplementary steps for the conversion of primary orsecondary amines of the present invention (Formula I wherein R and/or Rare hydrogen) into secondary or tertiary amines by reductive alkylation(Reaction 18) or reaction with an appropriate R or R halide or otherreactive ester suitable for the introduction of other R and R groups asdefined for Formula I according to known methods for the alkylation ofamines. The following examples are arranged to particularly describe themethods of the foregoing diagrams as follows.

Gramine SynthesisExamp1e 1-25. Vilsmeier Aldehyde SynthesisExample 26.Oxamyl Synthesis-Examples 27-43. Reductive Alkylation-Examples 44-74.Fischer Synthesis-Examples 75-83.

EXAMPLE 1 3- 2'-amino ethyl) -5-methanesulfonamidoindolemethanesulfonate (a) 5 methanesulfonamidoindoleacetonitrile. 5-

aminoindole-3acetonitrile is prepared by the reaction sequenceS-nitroindole, 5-nitrogramine, S-nitroindole 3- acetonitrile, and thencehydrogenation of a solution of 13.7 g. (0.068 mole) of the latter in 150ml. of ethanol at room temperature over 0.2 g. of platinum oxidecatalyst at 60 p.s.i. 5aminoindole-3acetonitrile is obtained in 88%yield, M.P. 129-135 C. To a cooled solution of 13.2 g. (0.077 mole) ofthe S-aminoindole-3-acetonitrile in 25 ml. of pyridine there is addeddropwise with stirring 8.9 g. (0.077 mole) of methanesulfonyl chloride.The reaction mixture is stirred at room temperature for 3 hrs. and thenwarmed to 6570 C. for 15 min. The product is recovered by pouring thereaction mixture into 500 ml. of ice water and collecting theprecipitate on a filter. It is washed with water, dissolved in 10%aqueous sodium hydroxide, and reprecipitated by acidification withhydrochloric acid, yield, 10.8 g. (57%), M.P. 157-158 C. An analyticalsample prepared by recrystallization from isopropanol exhibited meltingpoint 157-159 C.

Analysis.-Calcd. for C H N O S: C, 53.00; H, 4.45; N, 16.86; S, 12.86.Found: C, 52.94; H, 4.68; N, 16.61; S, 12.91.

(b) Hydride reduction.A solution of 5.0 g. (0.02 mole) of5-methanesulfonamidoindole-3acetonitrile in 50 ml. of drytetrahydrofuran is added in dropwise fashion to a stirred mixture of 2.3g. (0.06 mole) of lithium aluminum hydride in 75 ml. of drytetrahydrofuran. The mixture is refluxed for a period of 2 hrs. and thenstirred a NO as N-R4 N--R4 H II overnight at room temperature. Asolution of 4.6 ml. of water and 10 ml. of tetrahydrofuran is then addedto decompose the excess lithium aluminum hydride and the reactioncomplex. The mixture is filtered and the filtrate concentrated bydistillation at reduced pressure. The residue is dissolved in boilingethanol, insoluble material filtered, and the filtrate concentrated atreduced pressure. The residue is further purified by trituration withisopropyl ether to yield the product weighing 5 g., M.P. 77-95" C. Thismaterial is dissolved in methanol and acidified with methanesulfonicacid to provide 2.4 g. (35%) of the methanesulfonate salt of the desiredproduct, M.P. 229- 235 C. (dec.). This material is recrystallized fromhot methanol which is acidified with methanesulfonic acid, M.P. 235-237C. (dec.).

Analysis.Calcd. for C11H15N3O2S'CH3SO3H: C, 41.25; H, 5.48; N, 12.02; S,18.35. Found: C, 41.18; H, 5.71; N, 11.79; S, 18.06.

EXAMPLE 2 3 (2'-aminoethyl) -6methanesulfonamidoindole hydrochloride Themethod of Example 1(a) is applied to 6-nitroindole to provide6-methanesulfonamidoindoleacetonitrile in 60% yield, M.P. 132-134 C.after recrystallization from isopropyl alcohol.

Analysis.-Calcd. for C H N O S: C, 53.00; H, 4.45; N, 16.86; S, 12.86.Found: C, 52.92; H, 4.68; N, 16.81; S, 13.05. This material is thenreduced to 3-(2'-aminoethyl)6methanesulfonamidoindole as described inExample 1(b). In this instance the hydrochloride salt is preparedby-treatmnent of the crude product with an ethanolic solution ofhydrogen chloride. The product is obtained in 51% yield, which ispurified for analysis by recrystallization from methanol-isopropyl ethermixture, M.P. 218- 220 C.

Analysis.-Calcd. for C H N O S-HCI: C, 45.59; H, 5.57; S, 11.06. Found:C, 45.72; H, 5.68; S, 11.30.

In this preparation the intermediate 6-nitrogramine may alternatively beprepared by nitration of gramine according to the method of Hester, J.Org. Chem. 29, 1158 (1964). 4-Nitrogramine is also obtained by thisnitration method.

EXAMPLE 3 3 (2-amin0ethyl 4-methanesulfonamidoindole hydrochloride4-nitrogramine is prepared according to the method of Hester, loc. cit.,and converted to 4-nitroindole-3-acetonitrile, which is thenhydrogenated and mesylated as decribed in Example 1(a), yielding4-methanesulfonamidoindoleacetonitrile in 69% yield, M.P. 210214 C.(dec.). This material is then reduced as described in Example 1(b) toprovide the desired product in 16% yield, M.P.

7 8 234-236 C. (dec.) after recrystallization from methaminum hydrideaccording to the method of Example 1(b) nolisopropyl ether. to providethe desired product.

Analysis.-Calcd. for C H N O S-HCl: C, 45.59; H, By substitution ofdiethyl sulfate, n-propyl chloride, or 5.57; N, 14.49; S, 10.82. Found:C, 45.85; H, 5.73; N, n-butyl bromide for methyl iodide in Example 25,corre- 14.24; S, 10.82. 5 sponding 3-(2'-aminoethyl)-5-[N-(ethyl,n-propyl, or n- EXAMPLES 4-9 butyl)methanesulfonamido]indoles areobtained.

The procedure of Example 1(a) is applied to the fol- EXAMPLE 26 lowingnitroindoles to provide, after reduction of the correspondingmethanesulfonamidoindole acetonitrile in- 3 (2 ig g aifiga gztermediates according to Example 1(b), the 3-(2-amino- 10ethyl)-substituted-indole products listed in the following50116411afleslllfonamldolndole-3-caIb0Xa1dhydebl The Vilsmeier reagentis prepared by cooling 20 ml. of

TABLE I.3-(2-AMINOETHYL) SUBSTITUTED INDOLES Starting Material ProductSubstituents Example No:

4 T-nitroindole 7-rnethanesulfonamido.

5... 2-methyl-6-nitroindole G-methauesulfonamido 2-metllyl-2-methyl-5-nitroindole fi-rnethanesulionamido-2-metl1yl.

7.. 2-methyl-7-nitroindole 7-methanesullonamido-Z-methyl.

8 Z-(n-butyl)--nitroindolo 2-(n-butyl)-5-methanesulionamido.

9 2-(n-propy1)-6-nitroindole.... 6-methanesulfonamido-2-(n-propyl).

EXAMPLES 10-24 dimethylformamide in an ice-salt bath and then adding 5.0ml. (0.054 mole) of phosphorous oxychloride in drop- The procedure ofExample 1(a) is repeated substitutwise fashion with stirring during amin. period. A soluing various R -sulfonyl halides and anhydrides forthe tion of 10.0 g. (0.048 mole) of S-methanesulfonamidomethanesulfonylchloride specified in that example. The indole in 15 ml. ofdimethylformamide is then added in resulting 5-R-sulfonamidoindoleacetonitriles are then redropwise fashion during aperiod of 1 hr. Excess reagent duced by the method of Example 1(b) tothe correspondand reaction complex is then hydroyzed by treatment withing 3-(2'-aminoethyl)-5-R -sulfonamidoindoles ('Formua solution of 22 g.(0.054 mole) of sodium hydroxide in la I) listed in the table. ml. ofwater after the addition of crushed ice to the TABLEII.3-(2-AMINOETHYL)-5-R 'S ULFONAMID OINDOLE R -substituent of ExampleNo.: Starting Material Product Hexanesultonyl chloride 11..Beuzenesulfonyl chloride 12.. p-Toluenesulfonyl chloride... p yl. 13.-O-Chlorobenzenesulfonyl chloride o-Chlorophenyl. 14.-m-Bromobenzenesulfonyl bromide... 15- p-Fluorobenzenesultonylchloride.-. p-Flouorophenyl. l6 p-Methoxybenzenesulfonyl chloridep-Methoxyphenyl. 17.- a-Naphthylenesulfonyl chloride..-

a-Naphthyl. 18.- 2-Methoxynaphthylene-7-sultonyl chloride.2-methoxy-7-naphthyl. 19 2,5-dimethylbenzenesulfonyl chloride...2,5-dimethy1phenyl. 20.. 2,5-dich1orobenzenesult'onyl chloride2,5-dich1orophenyl. 21.. Methanesulfonic anhydride Methyl. 22.-m-Benzyloxybenzenesulfonyl brorm mBenzyloxyphenyI. 23.-p-Ethylbenzenesulionyl chl0ride.- p-Ethylphenyl. 24 Cyclohexauesultonylchloride Cyclohexyl.

EXAMPLE 25 reaction mixture. The resulting solution is heated toboiling, cooled to room temperature, acidified with concen-'ammoethyl)'5'(Nlmgtglylmethanesulfonamldo) trated hydrochloric acid,and the resulting precipitate colm 06 lected on a filter and washed withwater; yield, 8.4 g. 5-methanesulfonamidoindole 3 acetonitrile, 7.8 g. 0(66%), MP. 215-217 C. (dec.). A portion recrystal- (0.031 mole), isdissolved in ethanolic sodium hydroxide lized from ethanol for analysismelted at 219-221 C. solution prepared by diluting 3.5 ml. of 9.15 Nsodium (dec.). hydroxide with 250 ml. of ethanol. A solution of 4.0 ml.Analysis.calcd. for C H N o S: C, 50.41; H, 4.23; (0.062 mole) of methyliodide in 25 ml. of ethanol is then N, 11.76; S, 13.46. Found: C, 50.69;H, 4.50; N, 11.60; S, added in dropwise fashion with stirring at roomtem- 5 13.31.

perature. The mixture is stirred at room temperature for (b) 5methanesulfonamido 3-(2'-nitro-l'-propenyl)- 4 hrs. and then the solventremoved by distillation at reindole. 5 methanesulfonamidoindole3-carboxaldeduced pressure. The residue is triturated with water andhyde, 6.4 g. (0.027 mole), is mixed with m1. of nitrothe solid product,5-(N-methylmethanesulfonamido)inethane containing 0.5 g. of ammoniumacetate and heatdole-3-acetonitrile, is collected, yield, 6.5 g. This 70ed at for 16 hrs. The relatively insoluble carboxaldematerial is twicerecrystallized from isopropanol to yield hyde gradually dissolves,affording a homogeneous reacthe purified intermediate, M.P. 144-146 C.tion mixture. Subsequently the desired product com- Analysis.--Calcd.for C H N O S: C, 54.73; H, 4.98; mences to precipitate. At the end ofthe reflux period the N, 15.96; S, 12.18. Found: C, 54.54; H, 5.28; N,16.02; reaction mixture is cooled and the precipitated product S, 12.39.This material is then reduced with lithium alu- 75 collected byfiltration; yield, 6.2 g. (78%), MP. 268- 270 C. (dec.), after washingwith isopropanol and drying. A portion recrystallized from methanol foranalysis exhibited melting point 273-275 C. (dec.).

Analysis.Calcd. fOl' C12H13N304S: C, H, N, 14.23; S, 10.86. Found: C,48.91; H, 4.66; N, 14.05; S, 10.92.

(c) Hydride reduction-A mixture of 10.0 g. (0.034 mole) ofS-methanesulfonamidoindole-3-(2'-nitro-1'- propenyl)-indole and 200 ml.of dry tetrahydrofuran is added in portionwise fashion to a stirredsuspension of 5.4 g. (0.14 mole) of lithium aluminum hydride in 100 ml.of dry tetrahydrofuran. The mixture is refluxed for 24 hrs., cooled, anda solution of 11 ml. of water in 25 ml. of tetrahydrofuran is addedthereto in dropwise fashion. The mixture is then stirred for anadditional 30 min., and insoluble material collected by filtration. Theproduct is recovered from the filter cake by extraction with three 400ml. portions of boiling ethanol. The combined ethanolic extracts areacidified with ethanolic hydrogen chloride and then concentrated atreduced pressure. The residue remaining after evaporation of the solventis triturated with isopropanol, collected, and dried; yield, 3.5 g.(34%), M.P. 250-255 C. (dec.). This material is recrystallized from amethanol-isopropyl ether mixture affording 3(2'-aminopropyl)-S-methanesulfonamidoindole hydrochloride, M.P. 261-263C. (dec.).

Analysis.Calcd. for C H N O S'HCI: C, 47.44; H, 5.97; N, 13.83; S,10.55. Found: C, 47.46; H, 6.21; N, 14.13; S, 10.52.

The method of Example 26 (a) is equally applicable to othermethanesulfonamidoindoles to provide the corresponding aldehydes. Forexample, 6-methanesulfonamidoindole 3 carboxaldehyde and7-methanesulfonamidoindole-3-carboxaldehyde and 5(N-methylmethanesulfonamido)indole-3-carboxaldehyde may be prepared insimilar fashion. These aldehydes may be condensed with nitroethane asexemplified in Example 26 (b) to provide the corresponding 3(2-aminopropyl)methanesulfonarnidoindoles. In some instances thereduction can be better accomplished by catalytic means, such as withplatinum oxide catalyst, than it can by lithium aluminum hydridereduction as is illustrated in Example 26 (c). If a trial run accordingto the lithium aluminum hydride method yields the starting materialunreacted, that method is probably inapplicable. The recoverednitropropenyl starting material is then reduced catalytically to affordthe desired product. A variety of methanesulfonamidoindoles which may beemployed according to this method are described in copending applicationof W. A. Gould and A. A. Larsen, Ser. No. 492,836, filed October 4,1965. Nitromethane, l-nitropropane, and l-nitrobutane may be substitutedin the process of Example 26 (b) to afford 3- indolylnitrovinyl,-nitrobuteny1, and -nitropentenyl intermediates convertible into thecorresponding 3 indolylaminoalkyl compounds by reduction.

EXAMPLE 27 N-benzyl-N-methyl-S-methanesulfonamidoindole-3- oxalylamide(a) N-benzyl-N-methyl-5-nitroindole-3-oxalylamide. 5-nitroindole, 15.0g. (0.0925 mole), is dissolved in 450 ml. of anhydrous ether and treatedat C. with 25.0 g. (0.20 mole) of oxalyl chloride dissolved in 50 ml. ofether. Treatment is in dropwise fashion during a period of 1 hr. and isfollowed by an 18 hr. period at room temperature to allow completion ofthe reaction. The yellow precipitate, which is nitroindole 3 oxalylchloride, is then collected by filtration, mixed with 250 ml. oftetrahydrofuran, and treated in dropwise fashion with 45.0 g. (0.37mole) of benzylmethylamine dissolved in 50 ml. of tetrahydrofuran. Themixture is stirred overnight; by-product benzylmethylamine hydrochlorideis separated by filtration. The filtrate is concentrated to dryness, andthe residue washed first with ether and then with water before 10recrystallizing from ethanol; yield, 10.5 g. (34%), M.P. 215216 C.

Analysis.Calcd. for C H N O C, 64.09; H, 4.48; N, 12.46. Found: C,64.32; H, 4.73; N, 12.34.

(b) N benzyl N methyl 5-aminoindole-3-oxalylamide-The oxalylamidederivative described in (a) preceding, 3.6 g. (0.0106 mole), isdissolved in ml. of ethanol nad hydrogenated over 0.2 g. of platinumoxide catalyst until 0.0318 mole of hydrogen has been absorbed by thereaction. The catalyst is removed by filtration, and the filtrateconcentrated to a yellow oil which is employed in the next step withoutpurification.

(c) N-benzyl-N-methyl-S-methanesulfonamidoindole-3- 0xalylamide.Theaminoindole prepared in (b) preceding as a yellow oil, 0.0106 mole, istreated in 25 ml. of pyridine with 1.2 g. (0.0106 mole) ofmethanesulfonyl chloride with stirring. The mixture is stirred at roomtemperature for 2 hrs. and then warmed to 6070 C. It is then poured intoice water. This product separates as an oil. The aqueous layer isdecanted, and the oil is dissolved in 10% aqueous sodium hydroxide. Thesolution is filtered and acidified with concentrated hydrochloric acid.The product is again obtained as an oil, which is converted to a powderby boiling with benzene. The powder is crystallized from hot ethanol;yield, 0.9 g., M.P. -172 C.

Analysis.Calcd. for C H N O S: C, 59.21; H, 4.97; N, 10.90; S, 8.32.Found: C, 59.14; H, 5.24; N, 10.79; S, 8.47.

The product of Example 27(0) is then reduced to provide '3[2-(N-benzyl-N-methylamino)ethyl]-5-methanesulfonamidoindole by means ofa reducing agent such as sodium, propanol, a metal hydride, orcatalytically at from 1 to 4 atmospheres pressure employing 5%palladium-onbarium sulfate catalyst under acid conditions. Under thelatter conditions the N-benzyl group is lost by hydrogenolysis toprovide 3-(Z-methylarninoethyl)-5-methanesulfonamidoindole.

This method is convenient for the preparation of the compounds ofFormula I having a variety of R and R substituents, simply bysubstituting various amines for 'benzylmethylamine in the procedure ofExample 27 (a).

TABLE III.3(2-R LRfi-AMINOETHYL)5-METH ANE- iSiULFONAMIDOINDOLES[Examples 28-43] /R4 N Substituent of Product Amine 3 28 Diethylamine'N(C2H5)2 29 Indoline Example No.

30 N -methylpiperazine 31 N-benzylpiperazine 32 Pyrrolidine 33Piperidine 34 Hexamethyleneimino TABLE III.-Cutinued R4 N Substltuent ofExample Amine Product N0. R3

35 'lllialuorplrollne N-S 36 Morpholine N -O 37 Styrylamlue -NHCH=CHC H38 Nortropano N Z 39 Perhydroisoqulnollne N 40 Cyclohex-3-enylamine Ill41 Benzylamlne --NHOH 42 N-acetylcthylencdiamiue. NHCH CHzNHC H H 43fi-Naphthylarnine N 12 is collected on a filter and the filtrateconcentrated to afford a second crop of material affording a total yieldof 63% of the desired product, which on recrystallization fromethanol-isopropanol mixture exhibits melting point 140141 C.

Analysis.Calcd. for C H N O S: C, 54.12; H, 5.29; N, 10.52. Found: C,53.81; H, 5.68; N, 10.36.

(b) Reductive alkylation.A mixture of 3.5 g. (0.013 mole) of5-methanesulfonamidoindole-3acetone, 3.1 g. (0.026 mole) ofphenethylamine, 0.8 g. (0.013 mole) of acetic acid, and 0.2 g. ofplatinum oxide in 150 ml. of ethanol is hydrogenated at p.s.i. until0.013 mole of hydrogen have been absorbed. The catalyst is filtered, thefiltrate acidified with concentrated hydrochloric acid, and concentratedat reduced pressure. The residue, after removal of the solvent, istriturated with isopropanol, affording 3.6 g. (68%) of 5-methanesulfonamido-3-[2- (phenethylamino)propyl]-indole hydrochloride,which is recrystallized from isopropanol (charcoal treatment), M.P.188190 C.

Analysis.Calcd. for C H N O S-HCl: C, 58.88; H, 6.41; N, 10.30; S, 7.86.Found: C, 58.98; H, 6.43; N, 10.02; S, 7.88.

EXAMPLES 45-73 The following amines are substituted for phenethylamineon a chemically equivalent basis in the procedure of Example 44(b). Theproducts named in the table are obtained in analogous fashion byreductive alkylation according to that method.

TABLE IV.5-METHANESULFONAM1DO-3-(2-R -AMINOPROPYL)-INDOLES BY REDUC'llVEALKYLATION R -Substituent of Product Amine Example No.:

66 2-aminopyr1diuc 67.- Cyclohexyhnethylamine- (652.- l-amlnoadamantane2-aminobicyclo-[2,2,11-0ctane Z-aminomethylbicyclo-[2,2,1]octane..

2-amino-2-methyl-1-propanol 3-aminoazabicyclo-[2,2,2]octane1-(2-aminoethyl) pyrrole 1-(4-methoxyphenyl)-2-propyl.1-(3,4-dimethoxyphenyl)-2-propyl. Isopropyl. l-methyl-3-phenylpropyl.1-(3,4 methylenedl0xyphenyD-2-propyl. 2-(4-tolyl) ethyl.1-phenoxy-2-propyl.

2-indanyl.

Bicyclo-[2,2,1]eotane-2-yl.

2-blcyclo-[2,2,l]octylmethyl. Cyclohexyl. 1-(l-carboxy-Zmethyl)propyl.2-phenylcyclopropyl. Cyclopentylmethyl. Cyclopropyl. 1,3-dimethylbutyl.1,4-di1nethy1penty1.

2,2-diphcnylethyl.

3-methoxypropyl.

Phen

. l-naphthyl.

2-pyridyl.

Cyclohexylmethyl. l-adamantanyl. 1-hydroxy-2-methyl-2-propyl.Azabicyclo[2,2,2]oct-3-y1. 1-(2-aminoethyl) pyrrolidine.

72.- l-naphthylmethylamlne l-naphthylmethyl. 73Z-dimethylaminoethylamine 2-dimethylaminoethyl.

EXAMPLE 44 EXAMPLE 74S-methanesulfonarnido-Ii-[Z-(phenethylaminojpropyl]indole hydrochloride5-methanesulfonamido-3- (Z-isopropylaminoethyl) indole3-(Z-aminoethyl)-5-methanesulfonamidoindole, 5.0 g. (0.0198 mole), isdissolved in 100 ml. of absolute ethanol and 3.5 g. (0.06 mole) ofacetone is added thereto. The solution is then subjected to catalytichydrogenation at room temperature and a pressure of 2 atmospheresemploying platinum oxide catalyst. The calculated quantity of hydrogen(0.0198 mole) is absorbed in the course of 75 1 to 2 hrs., and theproduct is isolated by separation of the 13 catalyst and concentrationof the ethanolic solution in vacuo.

EXAMPLE 75 3-(Z-aminoethyl)-5-methanesulfonamidoindole-2- carboxylicacid hydrochloride (a) 2,3-dioxopiperidine 3p-nitrophenylhydrazone.--3-carbethoxy-Z-piperidone, 25.0 g. (0.147 mole), is kept overnight withan aqueous solution of 8.8 g. of potassium hydroxide in 450 ml. ofwater. A solution of pnitrobenzenediazonium chloride is then prepared bydissolving 22.4 g. of 4-nitroaniline in 450 ml. of hot Water containing37.5 g. of hydrogen chloride, with 12.5 g. of sodium nitrite dissolvedin 75 ml. of water. This solution is then clarified by filtration andadded to the piperidone solution, while maintaining the temperature at510 C. The mixture is stirred for 4 hr. at this temperature, at whichtime evolution of carbon dioxide has ceased. The precipitated product iscollected by filtration, washed with water, and dried; yield, 28.1 g.(77%), M.P. 230-235 C.

(b) 6 nitro 1,2,3,4 tetrahydro 9H pyrido[3,4b]- indol-1-one.--A mixtureof 60 g. of polyphosphoric acid and 10.0 g, (0.04 mole) of2,3-dioxopiperidine 3-p-nitrophenyl hydrozone is heated at 110 C. untilgas evolution ceases. The mixture is then mixed with 500 ml. of icewater and the solid precipitate collected on a filter. It isrecrystallized from 9:1 acetic acid-water, and then washed withisopropanol; yield, 6.4 g., fails to melt at 300 C.

(c) 6 amino 1,2,3,4 tetrahydro 9H pyrido[3,4b]- indol-1-one.--Theproduct of (b) preceding, 6.0 g. (0.026 mole), is hydrogenated over 0.5g. of platinum oxide catalyst employing 200 ml. of absolute ethanol asreaction medium. Hydrogenation is carried out at 60 psi. for a periodsufiicient to permit the consumption of 0.078 mole of hydrogen. Thereaction mixture is then heated to boiling and diluted with sufiicientethanol to dissolve the precipitated organic material. The catalyst isthen removed by filtration and the filtrate allowed to cool, resultingin crystallization of the product; weight, 2.5 g., M.P. 279- 281 C.(dec.). The filtrate is concentrated to provide additional crops ofmaterial for a total yield of 6.3 g. (84%).

(d) 6 methanesulfonamido 1,2,3,4 tetrahydro 9H- pyrido[3,4b]indol 1one.6 amino 1,2,3,4 tetrahydro 9H pyrido[3,4b]indol 1 one, 6.5 g.(0.0325 mole), is dissolved in 50 ml. of pyridine and treated indropwise fashion with 3.8 g. (0.0325 mole) of methanesulfonyl chloride.The mixture is stirred at room temperature for 4 hrs., heated to 6570 C.for 15 min, and then poured into 500 ml. of ice water. The product iscollected on a filter and purified by dissolving in aqueous 2 N sodiumhydroxide and reprecipitating by acidifying with concentratedhydrochloric acid. The product is collected, washed with water, anddried, yield, 7.7 g. (85% M.P. 279-281 C, (dec.). This material isrecrystallized from acetic acid-water, M.P. 282-283 C. (dec.).

Analysis.--Calcd. for C H N O S: C, 51.60; H, 4.69; N, 15.04; S, 11.48.Found: C, 51.68; H, 4.85; N, 15.01; S, 11.29.

(e) Hydrolysis-The product of (d) preceding, 2.8 g. (0.01 mole), isrefluxed overnight with a solution of 10 g. of potassium hydroxide in 40ml. of water and 60 ml. of ethanol. The mixture is cooled, filtered, andthe filtrate diluted with 300 ml. of water. Acidification withconcentrated hydrochloric acid results in precipitation of 3 (2aminoethyl) methanesulfonamidoindole 2- carboxylic acid hydrochloride;yield, 2.7 g. (78%), M.P. 282283 C. (dec.). This material isrecrystallized from methanol-isopropyl ether, M.P. 271.5272 C. (dec.).

AnalysiS.-Calcd, for CI2H15N3O4S'HCII C, H, 4.83; N, 12.59; S, 9.60.Found: C, 43.27; H, 4.92; N, 12.60; S, 9.52,

. EXAMPLE 76 3- (2-aminoethy1)-5-methanesulfonamido-l-methylindole-2-carboxylic acid hydrochloride (a) 6 nitro 9 methyl 1,2,3,4 tetrahydro9H- pyrido[3,4d]indole 1 one.--6 nitro 1,2,3,4 tetrahydro 9Hpyrido[3,4b] indol 1 one, 2.0 g. (0.0087 mole, Example 75 (b), isdissolved in 40 ml. of acetone containing 6 ml. of 20% aqueous potassiumhydroxide, heated to reflux, and 3.2 ml. of dimethylsulfate added, Theproduct appears as a yellow precipitate which is collected afterdiluting the reaction mixture with water. It is washed with water andthen with cold alcohol; yield, 2.3 g., M.P. 287-288 C. (dec.).

(b) 6 amino 9 methyl l,2,3,4 tetrahydro 9H- pyrido[3,4b]indol-1one.--Theproduct of (a) preceding, 13.3 g. (0.054 mole), is hydrogenated over 0.5g. of platinum oxide at 60 psi. employing 250 ml. of absolute ethanol asreaction medium. After absorption of 0.162 mole of hydrogen, thecatalyst is filtered and the residue concentrated by distillation of thesolvent. The residue is triturated with isopropanol and filtered; yield,9.6 g. (82%), M.P. 158-161 C.

(c) 6methanesulfonylamido-9-rnethyl-l,2,3,4-tetrahydro-9H-pyrido[3,4b]indol-1-one.Theproduct of (b) preceding, 3.8 g. (0.0175 mole), is dissolved in 35 ml.of pyridine and treated in dropwise fashion with 2.1 g. (0.0175 mole) ofmethanesulfonyl chloride. The mixture is stirred for 4 hrs. at roomtemperature and then warmed for 10 min. at 60-70 C. The product isrecovered by pouring the mixture into 500 ml. of ice water andfiltering. It is a light purple-colored solid which is dissolved indilute aqueous sodium hydroxide solution, filtered, and acidified withdilute hydrochloric acid. The precipitate is collected and Washed withwater; yield, 4.0 g. (79%), M.P. 265-268 C. (dec.), as obtained andafter recrystallization from acetic acid-water.

Analysis.--Calcd. for C H N O S: C, 53.23; H, 5.15; N, 14.33; S, 10.93.Found: C, 53.47; H, 5.32; N, 14.19; S, 11.00.

((1) Hydrolysis-The product of (c) preceding, 2.9 g. (0.01 mole), isrefluxed overnight with a solution of 10 g. of potassium hydroxide in 40ml. of water and 60 ml. of ethanol. The mixture is then cooled,filtered, and diluted to 300 ml. of water. The filtrate is acidifiedwith concentrated hydrochloric acid, the3-(2-aminoethyl)-5-methanesulfonamido-1-methylindole-2-carboxylic acidhydrochloride, which precipitates, is collected on a filter, washed withhydrochloric acid, and dried; yield, 3.1 g. (89%), M.P. 253-255 C.(dec.). This material is recrystallized from methanol-isopropyl ether,M.P. 243.5 C. (dec.) :3.

Analysis.Calcd. for C H N O S: C, 44.89; H, 5.21; N, 12.0; S, 9.22.Found: C, 45.03; H, 5.38; N, 11.96; S, 9.34.

EXAMPLE 77 3-(2-aminoethyl)-5-(N-methylmethanesulfonamido)indole-2-carboxylic acid (a) 6-(N-methylmethanesulfonamido)1,2,3,4-tetrahydro 9H pyrido[3,4b]indol-l-one.6 methanesulfonamido1,2,3,4 tetrahydro-9H-pyridol[3,4b]indol-1-one, 8.4 g. (0.03 mole,Example 75 (d)) is dissolved in 200 ml. of ethanol containing 0.031 moleof sodium hydroxide. A solution of 4.0 ml. of methyl iodide in 25 ml. ofethanol is then carefully added thereto. The mixture is stirred at roomtemperature for 20 hrs., filtered, the filter cake Washed with ethanol,and dried; yield, 7.4 g., M.P. 265- 273 C. This material is trituratedwith a small volume of aqueous 2 N sodium hydroxide, filtered, anddried; weight, 3.2 g., M.P. 217220 C. Approximately 3.7 g. of unreactedstarting material is recovered by acidification of the sodium hydroxidefiltrate. The product is recrystallized from acetonitrile to provide thepurified material, M.P. 226.5-228 C.

Analysis.-Calcd. for C H N O S: C, 53.23; H, 5.15; SN, 14.33; S, 10.93.Found: C, 53,49; H, 5.38; N, 14.55;

(b) Hydrolysis.-Tl1e product of (a) preceding is hydrolyzed withalcoholic potassium hydroxide as described 3,472,870 15 16 in Example 75(e) to provide the desired product in the wherein the group fashiondescribed there.

EXAMPLES 78-83 The following R -sulfonyl halides are substituted formethanesulfonyl chloride in the procedure of Example 5 s located 1n ther 7-P0S1tl0HS 0f the lhdOle 75(d). The resulting product is thenhydrolyzed according rlng and to procedure 75 (e) to give various3-(2-aminoethyl)-5- Alk is an alkylene group of 2 to 6 carbon atoms withR -sulfonamidoindole-2-carboxylic acids. Table V cona least two carbonatoms separating the ring and tains a listing of various sulfonylhalides that may be 10 the nitrogen a employed, and identifies theproduct resulting from this R is hydrogen, benzyl, or lower alkyl havingup to procedure. 4 carbon atoms,

TAB LE V.3-(2-AMINOETHYL)-5-R -S ULFONAMID OIND OLE- Z-CARB OXYLIC ACIDS R -Substituent Sulfonyl halide of Product Example N o:

78 Vinylsulfonyl chloride CH =CH- 79. Prop-2-enylsulfonyl chlorideCHZZCHCHP 80 Styrylsulfonyl chloride CtH CH=OH 83 Benzylsulfonylchloride C5H5CHz- The compounds of Formula I are amphoteric sub- R ishydrogen, carboxyl, or lower alkyl having up to stances, forming saltswith both acids and bases. These 4 carbon atoms,

salts are also considered part of the present invention and R ishydrogen, benzyl, lower alkyl, or lower alkenyl it is intended toinclude not only the pharmaceutically having up to 4 carbon atoms,

acceptable salts which have the physiological uses re- R is selectedfrom the g p consisting of hydrogen, ferred to above, but also othersalts, since they have utility alkyl, alkenyl, alkynyl, cycloalkyl andphenylalkyl, as intermediates in preparation of pharmaceutically preeachcontaining up to 12 carbon atoms,

ferred forms of the present products, including the free R is alkyl oralkenyl, each having up to 10 carbon base. For example, acid additionsalts with optically atoms, and

active acids such as D-camphorsulfonic acid, L- or R is hydrogen orlower alkyl having up to 4 carbon D-tartaric acid are useful forresolution of enantiomort and (b) the pharmaceutically acceptable phicpairs of the present compounds and are considered acid addition andmetal Salts of part of this invention. 2. The compound of claim 1 inwhich Alk is ethylene,

Examples of pharmaceutically acceptable acid addition R4 nd R arehydrogen atoms, and R is the salts include the hydrochloride,hydrobromide, acetate, methyl group. propionate, phosphate, nitrate,succinate, gluconate, mu-3-(Z-amiHOethYI)-4-methflneslllfonamidonindolecate, sulfate,methanesulfonatc, ethanesulfonate, p-tolu- 3-( y n n enesulfonate etc.salts. Pharmaceutically acceptable metal 5.3-(2-aminoethyl)-6-methanesulfonamidoindole.

salts include the sodium, potassium, lithium, magnesium, 6. The compoundof claim 1 wherein Alk is propylcalcium, barium, zinc, and aluminumsalts. The sulfoaniene, R R R R and R are hydrogen, and R is lide freebases of Formula I are also pharmaceutically methyl.

acceptable forms. 7. 3- (Z-aminopropyl)-5-methanesulfonamidoindole.

The present salts may be prepared in conventional fash- 8. The compoundof claim 1 wherein R R R and ion by treatment of one of the presentcompounds with an R are hydrogen, R is methyl, R is phenethyl, and Alkacid or base. For the preparation of salts with monobasic is propylene.

acids and monoacidic bases, use of equimolar quantities 9.S-methanesulfonamido 3 [2 (phenethylamino)- of the two reactants isconvenient. In the formation of propyl]indole.

salts of polyacidic bases and polybasic acids, it is con- ReferencesCited venient to reduce the molecular proportion of the acid or UNITEDSTATES PATENTS base so that but one chemical equivalent thereof 1semploymi 0 3,205,236 9/1965 Alla1s et a1. 260326.15

What is claimed is: 1. A compound of the group (a) having the formulaALEX MAZEL Pnmary Exammer J. A. NARCAVAGE, Assistant Examiner R 5 &A1kN\ U.S. Cl. X.R.

UNITED S"A ES PATENT OFFIQE CERTIFICATE OF CORRECTION :ent No. 3, l72,870 Dated October 1, 1969 Jent0r(s) AUBREY A. IARSEN and WILLIAM A.GOULD (deceased) BARBARA E. GOULD widow 8: legal rep. of the-estate ofWM. A. GOUI It is certified that error appears in the above-identifiedpatent :1 that said Letters Patent are hereby corrected as shown below:

,1. 2, line 2-9, "Genealized" should be Generalized line +8, after "COR"insert a comma ale. 2 bottom 1' page, REDUCTIVE ALKYLATION "R should a R""o 15. 3 bottom of page, REDUCEIVE ALKYLATION, "CH CHNHR 'should be casium 1. 5, line 37, "Example" should be Examples 1. 7, Table II, Example13, "0-chlorobenzenesulfonyl" should be o-chlorobenzenesulfonyl 1. 8,line 33, "hydroyzed" should be hydrolyzed :1. 10, line 8, nad" should beand line 75 Example n, should be 91. 11 Example 53, "cotane" should beoctane 01. 13, line 23, "hydrozone" should be hydrazone ol. 1%, line 19,"methanesulfonylamido" should be 5-- methanesulfonamido line 72, "53,49" should be 01. 15, Table V, Example 82, "enysulfonyl" should beenylsulfonyl Continued J GM. 15, 11:1: 65 (claim 1), 1n the tornu1a "RSO N" should be 001. 16, 1m 15 (china 3), "nethanuulfomnidonindole"should km nethnnoaultonnmidoindole SIGNED AND SEALED MAY 2 6 1970 MAttest:

Edward M.Fletche1',1r WIMIAII 2. 50mm, J1

Attestine Officnr 810her of Patent.

